The present invention relates to polymorphs of a substituted triazolo-phthalazine derivative, to their use in therapy, to compositions containing them and to processes for their manufacture. The present invention also relates to a pamoate formulation of the derivative and to new uses of pamoate ions.
We have now discovered that it is possible to obtain medicaments which have cognition enhancing effects which may be employed with less risk of proconvulsant effects previously described with benzodiazepine receptor partial or full inverse agonists. Inverse agonists which are inverse agonists for the xcex15 receptor and are relatively free of activity at xcex11, xcex12 and xcex13 receptor binding sites are preferred.
European Patent Applications 0085840 and 0134946 describe related series of 1,2,4-triazolo[3,4-a]phthalazine derivatives which are stated to possess antianxiety activity. However, there is no disclosure nor any suggestion in either of these publications of the compounds of the present invention, nor that the compounds disclosed in the Applications have any cognition enhancing properties.
The present invention provides 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine in the form of a dihydrate.
There is also provided 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine in the dehydrated form of the dihydrate.
There is further provided 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine in the form of a pentahydrate.
These polymorphs are new and may be advantageous, for example, for ease of processing, handling or dosing of the compound. They may, in particular, have improved chemical properties such as solubility, stability or rate of solution. In particular, they may be particularly suitable for manufacture of dosage forms. Examples of dosage forms are mentioned later.
International Patent Application No. PCT/GB98/01307 discloses 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3, 4-a]phthalazine which compound is useful for enhancing cognition. There is no specific disclosure or discussion of the crystal forms of this compound.
The dihydrate may be prepared by mixing a saturating amount of 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo [3,4-a]phthalazine with 5% aqueous di-sodium pamoate for several days. The dihydrate can be isolated by filtering the product.
The dihydrate may alternatively be produced by mixing a saturating amount of 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine with USP water. The solids obtained from filtering the product are partially in dihydrate form.
A further method of producing the dihydrate is to mill (i.e. nanonise) the anhydrous form of 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine in accordance with details disclosed in U.S. Pat. No. 5,145,684.
Another method for producing the dihydrate is to dissolve the anhydrous form in glacial acetic acid and water in about a 39:9 mixture, followed by hot filtration, the addition of a large amount of water of about four times the volume of the mixture, and ageing at room temperature for from 2 to 40 hours before filtration of the final product.
The dehydrate may be prepared by gentle heating of the dihydrate or pentahydrate in a vacuum oven from 30xc2x0 C. to 100xc2x0 C. for about 20.5 hours generally under dry nitrogen purge.
The pentahydrate may be produced by adding excess solid 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine to water or organic solvents with sufficient water present and generally stirring for several hours, such as about 12 hours, generally at room temperature. The pentahydrate can be isolated by filtering the product. Examples of water/organic solvents are ethyl acetate (saturated with water), acetonitrile (1/1 with water), acetic acid (20/80 with water), acetone (20/80 with water) and tetrahydrofuran (1/1 with water). The pentahydrate is preferably stored at humidities above 93%.